US10183010B2 - 2-oxo-1,2-dihydrobenzo[cd]indole compound and use thereof - Google Patents

2-oxo-1,2-dihydrobenzo[cd]indole compound and use thereof Download PDF

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US10183010B2
US10183010B2 US15/546,251 US201615546251A US10183010B2 US 10183010 B2 US10183010 B2 US 10183010B2 US 201615546251 A US201615546251 A US 201615546251A US 10183010 B2 US10183010 B2 US 10183010B2
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ethyl
dihydrobenzo
oxo
indol
indole
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US20180008574A1 (en
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Yong Xu
Xiaoqian XUE
Yan Zhang
Ming SONG
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Guangzhou Institute of Biomedicine and Health of CAS
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Definitions

  • the present invention relates to the technical field of chemical medicines, and specifically to a 2-oxo-1,2-dihydrobenzo[cd]indole compound and use thereof.
  • the bromodomain (BRD) family of proteins recognizes and binds to the acetylated lysine acting as a reader of lysine acetylation state. These “epigenetic readers” bind to acetyllysine residues on the tails of histones H3 and H4, and regulate chromatin structure and gene expression.
  • BRD bromodomain
  • BRD2 and BRD3 are reported to associate with histones along activity transcribed genes and may be involved in facilitating transcriptional elongation, while BRD4 appears to be involved in the recruitment of the P-TEFb complex to inducible genes, resulting in phosphorylation of RNApolymerase and increased transcription output.
  • BRD3 and BRD4 Chromosomal translocation of BRD3 and BRD4 to the nuclear protein in testis (NUT) locus generates BRD3-NUT or BRD4-NUT fusion protein that results in c-Myc overexpression and NUT midline carcinoma (NMC), an aggressive squamous cell malignancy unresponsive to conventional chemotherapeutics.
  • BRDT is uniquely expressed in the testes and ovary.
  • the first potent BET inhibitor was the diazepine JQ1 by nuclear magnetic resonance technology, subsequently, more molecues were reported by epigenetic screening and targeted biochemistry. By these potent inhibitors, more knowledge about the relationship of BET proteins and diseases was disclosed. Rapid progress in the development of bromodomain ligands has stimulated extensive interest and has led to several BET bromodomain inhibitors reaching clinical trials for cancers and inflammations.
  • the technical problem to be solved by the present invention is: providing a 2-oxo-1,2-dihydrobenzo[cd]indole compound, which is effective in inhibiting the BET bromodomain receptor and can be used as a therapeutic medicine for cancer, cell proliferation disorders, inflammatory diseases and autoimmune diseases, sepsis, viral infections.
  • R 1 is selected from H or C 1 -C 4 linear or branched alkyl
  • R 2 is selected from C 1 -C 7 alkyl, C 1 -C 4 alkylene-R 6 or C 0 -C 4 alkylene-R 7 -cyclic ring
  • R 6 is selected from —OR 8 , —COR 8 , —CONHR 8 , —COOR 8 , —S(O) m R 8 , —S(O) m R 8 , —NHCOOR 8 , —NHCOR 8 or —NH 2 , wherein m is 0 or 2, and R 8 is selected from hydrogen or C 1 -C 3 alkyl
  • R 7 is selected from —COR 9 , —COOR 9 , —OR 9 or unselected, wherein R 9 is selected from C 1 -C 3 alkylene
  • cyclic ring is selected from C 3 -C 10 cycloalkyl, phenyl, or
  • R 1 is selected from H or C 1 -C 4 linear or branched alkyl;
  • R 3 is selected from C 1 -C 7 alkyl, C 1 -C 4 alkylene-R 6 or C 0 -C 4 alkylene-R 7 -cyclic ring;
  • R 6 is selected from —OR 8 , —COR 8 , —CONHR 8 , —COOR 8 , —S(O) m R 8 or —S(O) m R 8 , wherein m is 0 or 2, and
  • R 8 is selected from hydrogen, C 1 -C 3 alkyl;
  • R 7 is selected from —COR 9 , —COOR 9 , —OR 9 or unselected, wherein R 9 is selected from C 1 -C 3 alkylene;
  • cyclic ring is selected from C 3 -C 10 cycloalkyl, phenyl, or heterocyclic group;
  • R 1 is selected from H or C 1 -C 4 linear
  • R 1 is selected from H or C 1 -C 4 linear or branched alkyl
  • R 5 is selected from C 1 -C 7 alkyl, C 1 -C 4 alkylene-R 6 or C 0 -C 4 alkylene-R 7 -cyclic ring
  • R 6 is selected from —OR 8 , —COR 8 , —CONHR 8 , —COOR 8 , —S(O) m R 8 , —S(O) m R 8 , —NHCOOR 8 or —NHCOR 8 , wherein m is 0 or 2, and R 8 is selected from hydrogen, C 1 -C 3 alkyl
  • R 7 is selected from —COR 9 , —COOR 9 , —OR 9 or unselected, wherein R 9 is selected from C 1 -C 3 alkylene
  • cyclic ring is selected from C 3 -C 10 cycloalkyl, phenyl, or heterocyclic group
  • the R 1 in formula I, II, III and IV is selected from H, methyl, ethyl, propyl, isopropyl or tert-butyl.
  • the cyclic ring in the C 0 -C 4 alkylene-R 7 -cyclic ring is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, phenyl, naphthyl, azetidine, oxetane, azacyclopentane, oxacyclopentane, azacyclohexane, oxacyclohexane, azacyclohexyl, imidazol-2-one ring, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrrolyl, piperazinyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, 1,3-dioxolanyl or benzo[d]thiazolyl, and these cycloxe, cycloprop
  • the cyclic ring in the C 0 -C 4 alkylene-R 7 -cyclic ring is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, phenyl, azetidine, oxetane, azacyclopentane, oxacyclopentane, azacyclohexane, oxacyclohexane, azacyclohexyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrrolyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, 1,3-dioxolanyl or benzo[d]thiazolyl, and these cycloalkyls are substituted by 0, 1, 2 or 3 group(s) selected from halogen, methyl, ethyl,
  • the cyclic ring in the C 0 -C 4 alkylene-R 7 -cyclic ring is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, phenyl, azetidine, oxetane, azacyclopentane, oxacyclopentane, azacyclohexane, oxacyclohexane, azacyclohexyl, imidazol-2-one ring, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrimidinyl, pyrrolyl, piperazinyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, 1,3-dioxolanyl or benzo[d]thiazolyl, and these cycloalkyls are substituted by 0, 1,
  • the cyclic ring in the C 0 -C 4 alkylene-R 7 -cyclic ring is selected from cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, phenyl, azetidine, oxetane, azacyclopentane, oxacyclopentane, azacyclohexane, oxacyclohexane, azacyclohexyl, imidazol-2-one ring, furyl, thienyl, oxazolyl, isoxazolyl, pyrrolyl, piperazinyl, tetrahydropyrrolyl, piperidinyl, morpholinyl, 1,3-dioxolanyl or 1H-indolyl, and these heterocyclic rings can be substituted by 0, 1, 2 or 3 group(s) selected from halogen, methyl,
  • C 1 -C 7 alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl or n-heptyl;
  • R 6 is selected from —OR 8 , —COR 8 , —CONHR 8 , —COOR 8 , —S(O) m R 8 , —S(O) m R 8 , —NHCOOR 8 and —NHCOR 8 , wherein m is 0 or 2, and R 8 is selected from hydrogen, methyl, ethyl, propyl, tert-butyl;
  • R 7 is selected from —COR 9 , —COOR 9 , —OR 9 or unselected, wherein R
  • C 1 -C 7 alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl or n-heptyl;
  • R 6 is selected from —OR 8 , —COR 8 , —CONHR 8 , —COOR 8 , —S(O) m R 8 , —S(O) m R 8 , —NHCOOR 8 or —NHCOR 8 , wherein m is 0 or 2, and R 8 is selected from hydrogen, methyl, ethyl, propyl, tert-butyl;
  • R 7 is selected from —COR 9 , —COOR 9 , —OR 9 or unselected, wherein R
  • C 1 -C 7 alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl;
  • R 6 is selected from —OR 8 , —COR 8 , —CONHR 8 , —COOR 8 , —S(O) m R 8 , —NHCOOR 8 or —NHCOR 8 , wherein m is 0 or 2, and R 8 is selected from hydrogen, methyl, ethyl, propyl or tert-butyl;
  • R 7 is selected from —COR 9 , —COOR 9 , —OR 9 or unselected, wherein R 9 is selected from C 1 -C 3 alkyl
  • C 1 -C 7 alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl or n-heptyl;
  • R 6 is selected from —OR 8 , —COR 8 , —CONHR 8 , —COOR 8 , —S(O) m R 8 or —NHCOOR 8 , —NHCOR 8 , wherein m is 0 or 2, and R 8 is selected from hydrogen, methyl, ethyl, propyl, tert-butyl;
  • R 7 is selected from —COR 9 , —COOR 9 , —OR 9 or unselected, wherein R 9 is selected from C 1 -C 3 alkyl
  • the compound of formula I, II, III, IV is selected from the group consisting of:
  • the present invention provides a method of treating a conditions or disease by administering a therapeutically effective amount of compounds of structural formula I, II, III, IV or pharmaceutically acceptable salts, isomers, racemates, prodrugs, cocrystalline complexes, hydrates, and solvates thereof.
  • the disease or condition of interest is treatable by inhibition of BET bromodomains, for Example, a cancer, a cellar proliferative disorder, an inflammatory condition, an autoimmune disorder, sepsis, or a viral infection.
  • the disease to be treated by a compound and method of the present invention is cancer.
  • treatable cancers include, but are not limited to, adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, actue promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cellieukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alve
  • the present invention provides a method of treating a benign proliferative disorder, such as, but are not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castleman disease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenic granuloma, and juvenile polyposis syndrome.
  • a benign proliferative disorder such as, but are not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granul
  • the compounds and methods of the present invention also treat infectious and noninfectious inflammatory events and autoimmune and other inflammatory diseases by administration of an effective amount of a present compound to a mammal, in particular a human in need of such treatment.
  • autoimmune and inflammatory diseases, disorders, and syndromes treated using the compounds and methods described herein include inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendictitis, pancreatitis, cholocystitus, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irrtiable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma
  • the invention further provides a method for treating viral infections and diseases.
  • viral infections and diseases treated using the compounds and methods described herein include episome-based DNA viruses including, but not limited to, human papillomavirus, Herpesvirus, Epstein-Barr virus, human immunodeficiency virus, hepatis B virus, and hepatitis C virus.
  • a compound of structural formula I, II, II, IV can be administered by any suitable route, for Example by oral, buccal, inhalation, sublingual, rectal, vaginal, intracisternal or intrathecal through lumbar puncture, transurethral, nasal, percutaneous, trans dermal, or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection and/or surgical implantation at a particular site) administration.
  • the present invention provides a combination of drugs of structural formula I, II, III, IV or pharmaceutically acceptable salts, isomers, racemates, prodrugs, cocrystalline complexes, hydrates, and solvates thereof.
  • the composite can be showed as liquid, semi-liquid or solid form.
  • the method is suitable for the way the medicine is used.
  • the composite can be administered by any suitable route, for Example by oral, parenteral, intraperitoneal, intravenous, subcutaneous, sublingual, intramuscular, rectal, buccal, intranasal, liposome.
  • the oral composite can be showed as solid, gel or liquid form.
  • Solid formulations include, but are not limited to, tablets, capsules, granules and bulk powder. These formulations can contain adhesive, thinner, disintegrant, lubricant, flux, sweetener and deodorant.
  • Adhesive include, but are not limited to, microcrystalline cellulose, glucose solution, Arabic jelly, gelatin solution, sucrose and starch paste;
  • Lubricant include, but are not limited to, talc, starch, magnesium stearate, calcium stearate, stearic acid;
  • Thinner include, but are not limited to, lactose, sucrose, starch, glycose and dicalcium phosphate;
  • Flux include, but are not limited to, silicon dioxide;
  • Disintegrant include, but are not limited to, crosslinked carboxymethyl cellulose sodium, starch hydroxyacetate, alginate, corn starch, potato starch, methyl cellulose, AGAR and carboxymethyl cellulose.
  • the composite can be formulated for parenteral administration by injection, e.g., intravenous, intramuscular or intravenous injection.
  • Injection can be made as pharmaceutically acceptable forms, e.g., liquid, solution or suspension, a solid form suitable for dissolving or suspending in a liquid prior to injection or an emulsion.
  • the composite can be readily combined with pharmaceutically acceptable carriers well-known in the art, e.g., waterborne carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, suspensions and dispersants, emulsifiers, chelating agents and other pharmaceutically acceptable substances.
  • Waterborne carriers include, but are not limited to, sodium chloride injection, forest gel injection, isotonic glucose injection, sterile water injection, glucose and lactated Ringer's injection;
  • Non-aqueous carriers include, but are not limited to, fixed oil, cottonseed oil, corn oil, sesame oil and peanut oil;
  • Antimicrobial agents include, but are not limited to, M-cresol, benzyl alcohol, chlorobutanol, benzalkonium chloride;
  • Isotonic agents include, but are not limited to, sodium chloride and glucose; Buffers include, but are not limited to, phosphate and citrate.
  • the composite can be formulated for sterile lyophilized powder injection.
  • the composite can be dissolved in sodium phosphate buffer solution (include glucose or other suitable excipient), and then the solution was sterile filtered, followed by lyophilization to give the desired formulation.
  • sodium phosphate buffer solution include glucose or other suitable excipient
  • the present invention provides compounds of a novel 2-oxo-1,2-dihydrobenzo[cd]indole as scaffold; These compounds can inhibite BET bromodomain protein.
  • Diseases and conditions treatable by a method of the present invention include, but are not limited to, cancers and other proliferative disorders, inflammatory diseases, sepsis, autoimmune disease, and viral infectios.
  • any variable e.g., R 1 , R 2 , etc.
  • the definition of each occurrence is independent of the other occurrence of each occurrence.
  • a combination of substituents and variables is allowed, as long as the combination stabilizes the compound.
  • the lines from the substituents into the ring system indicate that the indicated bond can be attached to any of the substitutable ring atoms. If the ring system is a polycyclic, it means that the bond is only attached to any suitable carbon atom adjacent to the ring.
  • C1-C4 in the “C1-C4” alkyl group includes a group having 1, 2, 3, 4 carbon atoms in a straight chain or branched chain.
  • the “C1-C4” alkyl group specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and isobutyl.
  • alkyl, cycloalkyl and heterocyclyl substituents may be unsubstituted or substituted.
  • the C1-C4 alkyl group may be substituted by one, two or three substituents selected from halogen, methyl, ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl, cyano, amino, phenyl diazenyl, —CONH 2 , —COOR, —COR 7 , —OR 7 , —NHCOR 7 , —NHCOOR 7 , —C 6 H 5 R 8 , morpholinyl, piperidinyl, tetrahydrofuranyl, pyridyl, wherein R 7 is selected from C1-C4 alkyl, phenyl; R 8 is optionally substituted with a substituent selected from C1 to C4 alkyl, halogen, acetyl, methoxy, ethoxy.
  • the present invention includes compounds of formulas I, II, III, IV, and their pharmaceutically acceptable salts and stereoisomers thereof.
  • Pharmaceutically acceptable salts include not only exemplary salts of specific compounds described herein, and also included pharmaceutically acceptable salts from compounds of formula I, II, III, IV or the free form of the compound-specific salt can be isolated using techniques known in the art. For Example, when treated with a suitable dilute aqueous solution of dilute aqueous solution, such as NaOH, K 2 CO 3 , dilute aqueous ammonia, and NaHCO 3 , the free form of formula I, II, III, IV was regenerated.
  • the free form may be different from salt forms in some physical properties, such as the dissociation in polar solvents, but for the purposes of this invention, the acid salts and base salts are comparable to their respective free forms in other pharmaceuticals.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from compounds containing the basic or acidic moiety by conventional chemical methods.
  • the salt of the basic compound is prepared by ion exchange chromatography, or free base with reaction of stoichiometric or excess amount of inorganic/organic acid in a suitable solvent or combination of a plurality of solvents.
  • salts of acidic compounds are formed by reaction with an appropriate inorganic/organic base.
  • the pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts by the reaction of a compound of the present invention with an inorganic or organic acid.
  • conventional non-toxic salts include those derived from inorganic acids, e g. from hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid; from organic acids, e g.
  • acetic acid propionic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, picric acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, water 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionate, trifluoroacetic acid.
  • conventional non-toxic salts include those derived from inorganic bases, e g. from aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts and zinc salts.
  • ammonium salts calcium salts, magnesium salts, potassium salts and sodium salts; from organic bases, e g., from primary amine, secondary amine, tertiary amine and naturally substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylamino ethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxypropylamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, guanza, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropyl
  • the compounds of the present invention can be prepared using the reactions shown in the following schemes. Accordingly, the following illustrative protocols are for illustrative purposes and are not intended to be limited to the listed compounds or any particular substituents. The number of substituents shown in the scheme is not necessarily to be used in the claims. For the sake of clarity, monosubstituted group is attached to a compound showed in invention which is allowed to have a plurality of substituents under the definitions of the formulas I, II, III, IV.
  • the compounds may be prepared by reacting the 1,8-naphthalenedicarboxylic anhydride as a starting material in 6 steps:
  • the compounds may be prepared by reacting the 1,8-naphthalenedicarboxylic anhydride as a starting material in 6 steps:
  • the compounds may be prepared by reacting the 1,8-naphthalenedicarboxylic anhydride as a starting material in 6 steps:
  • the compounds may be prepared by reacting the 1,8-naphthalenedicarboxylic anhydride as a starting material in 5 steps:
  • 1,8-naphthalenedicarboxylic anhydride (11.9 g, 0.06 mol) and hydroxylamine hydrochloride (4.18 g, 0.06 mol) were combined as a solution in pyridine (70 mL).
  • the reaction was conducted under reflux for 1 h followed by cooling to 80° C.
  • To the reaction system mixture was added powdered p-toluenesulfonyl chloride (22.88 g, 0.12 mol). After the addition, the reaction was performed under reflux for 1 h. After cooling to room temperature, the reaction mixture was poured into ice water (200 mL) and stirred to precipitate crystals.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • 1 H NMR 400 MHz, d-DMSO
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • 1 H NMR 400 MHz, d-DMSO
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • the synthesis can refer to Example 1.
  • 6-amino-1-ethylbenzo[cd]indol-2(1H)-one can refer to Example 1.
  • the synthesis can refer to Example 46.
  • 6-amino-1-ethylbenzo[cd]indol-2(1H)-one can refer to Example 1.
  • the synthesis can refer to Example 56.
  • the synthesis can refer to Example 56.
  • the synthesis can refer to Example 67.
  • the synthesis can refer to Example 67.
  • tert-butyl 3-(1-ethyl-2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamido)pyrrolidine-1-carboxylate can refer to 84.
  • the synthesis can refer to Example 67.
  • the synthesis can refer to Example 67.
  • the synthesis can refer to Example 67.
  • the synthesis can refer to Example 67.
  • the synthesis can refer to Example 67.
  • the synthesis can refer to Example 67.
  • the synthesis can refer to Example 67.
  • the synthesis can refer to Example 67.
  • the synthesis can refer to Example 67.
  • the synthesis can refer to Example 67.
  • Activity test in vitro the compounds of the present invention were conducted the AlphaScreen assay to confirm the ability of a ligand to disrupt the interaction of BRD(1) and its SRC1-4 peptide.
  • BRD4(1) protein 500 nM; buffer, (10 ⁇ ) MOPS (500 mM), CHAPS (0.5 mM), NaF (500 mM), BSA (1 mg/mL), PH (7.4); streptavidin donor beads 50 ⁇ g/mL, nickel acceptor beads 50 ⁇ g/mL, BRD4(1) ligand, biotinylated SRC1-4 peptide, H4KAc4-botin (SGRG ⁇ Lys-Ac ⁇ GG ⁇ Lys-Ac ⁇ GLG ⁇ Lys-Ac ⁇ GGA ⁇ Lys-Ac ⁇ RHR ⁇ Lys(biotin) ⁇ ) 50 nM.
  • 150 ⁇ L mix system BRD4(1) protein, 15 ⁇ L; buffer, 15 ⁇ L; ddH 2 O, 15 ⁇ L; compound, 15 ⁇ L; streptavidin donor beads, 15 ⁇ L; nickel acceptor beads, 15 ⁇ L; positive compound, (+)-JQ1.
  • the BRD4(1) protein and biotinylated SRC1-4 peptide were added in ddH2O and buffer.
  • the reaction mixture was incubated at 20° C. for 1.5 h, streptavidin donor beads and nickel acceptor beads was added.
  • the reaction mixture was incubated at 20° C. in dark for 1 h.
  • the reaction mixture (40 ⁇ L) was transferred to 384 well plates, and tested by PE Envison2104 multifunctional detection of microplate reader. Excitation wavelength, 680 nM; Emission wavelength, 520-620 nM.
  • BRD4(1) protein 100 ⁇ M; compounds, 400 ⁇ M, buffer, (10 ⁇ ) MOPS (50 mM), NaCl (150 mM), glycerin 10%, PH (7.5); Sypro Orange Protein Gel Stain (500 ⁇ ).
  • Mix system BRD4(1) protein, 2 ⁇ L; Sypro Orange Protein Gel Stain (500 ⁇ ), 2 ⁇ L; compound, 10 ⁇ L; buffer, 2 ⁇ L; ddH 2 O, 2 ⁇ L, positive compound, (+)-JQ1.
  • the 10 ⁇ L reaction mix was added to 96-well PCR plates.
  • SYPRO Orange (Sigma) was added as a fluorescence probe at a dilution of 1:1000 and incubated with compounds on ice for 30 min. The total DMSO concentration was less than 2%.
  • the TSA was carried out using the Bio-Rad CFX96 Real-Time PCR System. The temperature was raised at a step of 0.5° C. per minute from 30° C. to 80° C. The fluorescence readings were recorded at a 0.5° C. interval, and obtained the ⁇ Tm.
  • the results come from the AlphaScreen assay and TSA assay in table 1-4.
  • Example 1 The activities of compounds of formula I AlphaScreen TSA Compounds ( ⁇ M) ⁇ Tm (° C.) (+)-JQ1 0.18 11.5
  • Example 1 0.53 7.4
  • Example 2 0.51 7.1
  • Example 3 1.08 7.5
  • Example 4 0.52 8.5
  • Example 5 0.14
  • Example 6 1.70 6.5
  • Example 7 0.84
  • Example 8 0.24 9.5
  • Example 9 0.41 9.5
  • Example 10 1.68 8
  • Example 11 2.08 5.5
  • Example 12 5.59 6.5
  • Example 13 6.29 6.0
  • Example 14 5.71 6.5
  • Example 15 6.05 3.0
  • Example 16 4.00 5.0
  • Example 17 2.27 7.0
  • Example 18 0.56 9.0
  • Example 19 0.47 9.5
  • Example 20 1.25 7.0
  • Example 21 0.34 8.1
  • Example 22 2.56 5.7
  • Example 23 3.7 2.4
  • Example 24 1.84 4.2
  • Example 25 8.17 4.2
  • Example 26 12.97 3
  • Example 27 3.13
  • Example 28 3.
  • the compounds of the present invention especially Examples 1, 2, 3, 4, 5, 8, 9, 10, 17, 18, 19, 20, 21, 30, 31, 78, 97, 99 and 100, showed similar potent when compared (+)-JQ1.
  • the compounds of the present invention were chemically stable and easily prepared when compared positive compound.

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CN109665987B (zh) * 2018-12-28 2022-02-18 河南大学 萘内酰亚胺-多胺缀合物及其制备方法和用途
CN113677664A (zh) * 2019-04-12 2021-11-19 C4医药公司 Ikaros和aiolos的三环降解物
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JP2023538520A (ja) * 2020-08-07 2023-09-08 シーフォー セラピューティクス， インコーポレイテッド Ｉｋａｒｏｓ又はａｉｏｌｏｓによって媒介される障害に対する有利な治療法
CA3194351A1 (en) * 2020-10-14 2022-04-21 Christopher G. Nasveschuk Tricyclic compounds to degrade neosubstrates for medical therapy
WO2023154417A1 (en) * 2022-02-09 2023-08-17 C4 Therapeutics, Inc. Morphic forms of cft7455 and methods of manufacture thereof

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4728663A (en) * 1986-01-13 1988-03-01 American Cyanamid Company N-[(1H-imidazol-1-yl)alkyl]benz[cd]-indol-2-amines and use in inhibiting thromboxane synthetase enzyme
US5081131A (en) * 1986-01-13 1992-01-14 American Cyanamid Company Omega-((hetero)alkyl)benz(cd)-indol-2-amines
CN1062904A (zh) 1990-09-17 1992-07-22 阿古龙制药有限公司 抗增生的取代萘化合物
JP2003137866A (ja) 2001-11-01 2003-05-14 Sankyo Co Ltd フェニレンジアミン誘導体
WO2007050795A2 (en) 2005-10-25 2007-05-03 Alvine Pharmaceuticals, Inc. Transglutaminase inhibitors and methods of use thereof
US20070105835A1 (en) 2005-11-07 2007-05-10 Kazantsev Aleksey G Compositions and methods for modulating poly(ADP-ribose) polymerase activity
WO2009016081A2 (en) 2007-08-02 2009-02-05 Actar Ab Benzoind0l-2-one derivatives for use in therapy
US7615563B2 (en) 2003-08-08 2009-11-10 Gonzalez Iii Jesus E Compositions useful as inhibitors of voltage-gated sodium channels
WO2014173241A1 (en) 2013-04-26 2014-10-30 Beigene, Ltd. Substituted5-(3,5-dimethylisoxazol-4-yl)indoline-2-ones
CN104530014A (zh) 2013-12-25 2015-04-22 中国科学院广州生物医药与健康研究院 2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺类化合物及其组合物和应用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR084070A1 (es) * 2010-12-02 2013-04-17 Constellation Pharmaceuticals Inc Inhibidores del bromodominio y usos de los mismos
UA119848C2 (uk) * 2013-03-15 2019-08-27 Інсайт Холдинґс Корпорейшн Трициклічні гетероцикли як інгібітори білків бет
US9290514B2 (en) * 2013-07-08 2016-03-22 Incyte Holdings Corporation Tricyclic heterocycles as BET protein inhibitors

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4728663A (en) * 1986-01-13 1988-03-01 American Cyanamid Company N-[(1H-imidazol-1-yl)alkyl]benz[cd]-indol-2-amines and use in inhibiting thromboxane synthetase enzyme
US5081131A (en) * 1986-01-13 1992-01-14 American Cyanamid Company Omega-((hetero)alkyl)benz(cd)-indol-2-amines
CN1062904A (zh) 1990-09-17 1992-07-22 阿古龙制药有限公司 抗增生的取代萘化合物
JP2003137866A (ja) 2001-11-01 2003-05-14 Sankyo Co Ltd フェニレンジアミン誘導体
US7615563B2 (en) 2003-08-08 2009-11-10 Gonzalez Iii Jesus E Compositions useful as inhibitors of voltage-gated sodium channels
WO2007050795A2 (en) 2005-10-25 2007-05-03 Alvine Pharmaceuticals, Inc. Transglutaminase inhibitors and methods of use thereof
US20070105835A1 (en) 2005-11-07 2007-05-10 Kazantsev Aleksey G Compositions and methods for modulating poly(ADP-ribose) polymerase activity
WO2009016081A2 (en) 2007-08-02 2009-02-05 Actar Ab Benzoind0l-2-one derivatives for use in therapy
WO2014173241A1 (en) 2013-04-26 2014-10-30 Beigene, Ltd. Substituted5-(3,5-dimethylisoxazol-4-yl)indoline-2-ones
CN104530014A (zh) 2013-12-25 2015-04-22 中国科学院广州生物医药与健康研究院 2-氧代-1,2-二氢苯并[cd]吲哚-6-磺酰胺类化合物及其组合物和应用

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Begley et al., "Fragment-based discovery of novel thymidylate synthase leads by NMR screening and group epitope mapping", Chem Biol Drug Des, vol. 76, May 17, 2010, pp. 218-233.
Gonzalez et al (2006): STN International, HCAPLUS database (Columbus, Ohio), Accession No. 2006: 103871. *
Kazantsev et al (2007): STN International, HCAPLUS database (Columbus, Ohio), Accession No. 2007: 507490. *
Shibata et al (2003): STN International, HCAPLUS database (Columbus, Ohio), Accession No. 2003: 366795. *
Xue et al, "Discovery of Benzo[cd]indo1-2(1H)-ones as Potent and Specific BET Bromodomain Inhibitors: Structure-Based Virtual Screening, Optimization, and Biological Evaluation", Journal of Medicinal Chemistry, vol. 59, Jan. 5, 2016, pp. 1565-1579.
Zhang et al., "Discovery of 2-oxo-1,2-dihydrobenzo[cd]indole-6-sulfonamide derivatives as new RORγ inhibitors using virtual screening, synthesis and biological evaluation", European Journal of Medicinal Chemistry, vol. 78, Mar. 22, 2014, pp. 431-441.

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022249120A1 (ko) * 2021-05-28 2022-12-01 삼진제약주식회사 신규한 벤조인돌론 화합물 및 이를 포함하는 약학적 조성물

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